Response of EIF2AK4 (GCN2) to amino acid deficiency (Homo sapiens)

From WikiPathways

Revision as of 16:14, 9 October 2020 by ReactomeTeam (Talk | contribs)
(diff) ←Older revision | Current revision (diff) | Newer revision→ (diff)
Jump to: navigation, search
1, 8, 9, 11, 14...46, 485364, 32, 38, 44, 502210, 13, 18, 20, 452, 404, 4412, 13, 18, 24, 25, 38...3, 6, 34, 38, 42...7, 17, 38, 46, 5036, 38, 506, 42, 46, 49nucleoplasmcytosolRPL10L RPL15 RPS29 RPL31 IMPACT RPL18 RPL6 RPS25 RPS27A(77-156) RPL5 RPL23 RPL36A RPL39 RPL7A RPL19 GCN1 RPL23 ATF4:CEBPB,CEBPG:ASNS geneRPS5 RPS16 RPL28 RPS15A RPS10 RPL39 RPL23A RPL24 RPL39L 28S rRNA RPL36 RPS4Y2 RPSA RPL15 RPL22 RPS4X RPS17 ATF3 geneRPS27A(77-156) RPL10 TRIB3 geneRPL9 RPS28 RPL26 RPS6 RPL39L ATF4dimer:p-T69,T71-ATF2 dimer:DDIT3 geneCEBPB RPL39 RPL10A RPL41 RPS12 RPS4Y2 ATF3RPS25 RPS11 DDIT3 RPL39L RPL37 CEBPB CEBPG RPS15A RPS8 CEBPB geneRPL36AL RPS27L ATF4RPL3 ATF4:CEBPB,CEBPG,DDIT3:TRIB3 geneRPL26 FAU RPL37 RPL21 p-T69,T71-ATF2RPL13 RPL23 GCN1 RPL6 RPL35A RPL34 RPS17 p-T69,T71-ATF2 EIF2S3 RPL26L1 RPS12 RPL37A RPS9 RPS23 EIF2AK4:GCN1:80Sribosome:mRNARPL29 GCN1 5S rRNA RPL3L RPL40 RPL23A RPL3 RPL4 RPL3L RPLP1 RPSA RPS28 RPS4X RPS16 RPLP2 RPL4 RPL4 RPS15 RPL29 RPL35A TRIB3 gene RPL32 ATF4 RPL7 RPS24 RPS23 RPL26 RPL7A RPL21 RPS17 ADPRPL7A RPL35 RPL7 RPL36AL RPL23 ATPCEBPB RPL18A CEBPB,CEBPG,DDIT3RPL19 RPS19 RPS14 RPL14 RPS14 RPL31 RPS3 RPL11 RPS23 RPL24 RPS28 RPSA RPL40 RPS3A RPL18A RPS11 RPLP2 RPL17 RPS13 RPS4X RPL35 RPL29 mRNA RPL11 RPL36A RPL13A RPS13 tRNA RPS15 RPS27 RPL10L RPS9 RPL15 RPS29 RPL30 18S rRNA RPL26 RPL22L1 RPS26 RPL6 RPL35A RPS24 RPL38 RPS14 RPL9 RPS3 RPL14 RPS4X RPL22 RPL34 RPL34 RPS8 RPL3L RPL5 RPS26 RPLP0 RPS7 RPL24 IMPACTRPL27A RPL10 RPS4Y1 RPL15 CEBPBRPS27L RPL15 RPL26L1 5S rRNA RPS10 RPS5 RPL7 DDIT3RPL36 5S rRNA RPL24 18S rRNA RPS29 RPS23 CEBPB gene EIF2S2 RPS2 RPS13 RPL19 RPS5 RPL8 RPL12 RPS21 GCN1:80Sribosome:mRNARPL26L1 RPL18A RPS20 RPS27A(77-156) p-S52-EIF2S1:EIF2S2:EIF2S3RPL39 RPL13 RPL35A RPL5 RPL17 RPS27 RPLP0 RPL7A RPS16 RPL18 RPL21 RPL12 RPL14 RPL28 RPL18 RPL22 RPS18 RPS6 RPL22 RPL27A RPL12 RPL27A RPL13A ADPRPL30 RPL35 RPL32 RPL8 RPS20 RPL9 RPL40 RPS19 RPS7 tRNARPL39L RPL41 tRNA:p-T899-EIF2AK4:GCN1:80S Ribosome:mRNARPL32 RPS21 18S rRNA mRNA 5S rRNA RPS20 IMPACT:GCN1:80Sribosome:mRNARPS4Y2 RPL13A RPL36A RPS7 RPS15 ASNSRPLP2 RPL22L1 RPS24 RPL22 RPS26 mRNA RPL21 RPL11 RPS4Y2 RPL28 RPL26L1 RPS27L RPS2 FAU RPS3A RPS12 tRNA RPL27 RPL23A RPL27 RPL27A RPLP0 RPS27 RPL36AL RPL30 RPS16 RPS27 RPL19 RPL37A 5.8S rRNA RPS27 RPL41 RPS20 RPL34 RPS15A RPS6 RPS2 RPL5 RPL29 RPL13A ATF4:CEBPB geneATF4:ATF3 geneRPL30 ATPRPL31 RPL3 RPS18 RPL18 RPS9 RPL10A RPS18 RPL3L EIF2S2 RPS26 mRNA RPL7 RPS3 28S rRNA RPLP0 ATF4 RPLP1 RPL27 RPS15A RPL4 RPS13 RPL30 RPL18 RPS11 RPL39 RPS18 RPL6 RPL8 RPL31 RPL14 EIF2AK4 RPL18A RPL38 RPL27 RPS27A(77-156) RPL36A RPS6 RPL27A RPL37 5.8S rRNA RPLP1 FAU RPS19 RPL31 RPS3 RPS3A RPL17 RPS25 RPL40 RPL12 RPS10 RPL26L1 RPL28 RPL35 RPS4X RPL40 RPL7 RPL37A 5S rRNA RPS28 CEBPG RPL3 RPL41 RPL23 DDIT3 gene RPL7A RPS21 RPSA RPL27 RPS11 RPS24 RPL36 RPL10L ASNS geneRPL37 RPL11 RPL10A RPL10 RPS5 RPS29 RPS17 RPS4Y1 RPL24 RPLP1 RPL23A RPL22L1 EIF2S1 RPS21 RPL22L1 RPL36 RPS27L ATF4 ASNS gene mRNA RPL14 RPL37A ATF4 mRNARPS2 RPL10L RPS14 RPS10 RPL4 RPS13 RPS8 RPS14 RPL36A RPL17 RPL13 tRNA:EIF2AK4:GCN1:80S Ribosome:mRNA28S rRNA RPS29 RPS4Y1 p-S52-EIF2S1 RPL28 RPL10L RPL3L EIF2AK4 18S rRNA RPS27A(77-156) RPS28 RPS20 RPS21 RPL10 RPL34 RPS16 RPS15 RPS9 CEBPB,CEBPGRPS17 RPS19 RPS12 RPL13 RPL9 RPL32 DDIT3 RPS26 p-T899-EIF2AK4 RPL8 RPL41 5.8S rRNA RPLP2 RPS15 ATF3 gene RPL10A RPS25 RPS4Y1 RPL37 RPS9 DDIT3 geneRPL10 TRIB3ATF4 RPS8 RPL35A RPS27L 5.8S rRNA RPL37A RPS23 EIF2S3 RPL22L1 RPS4Y2 RPL36AL 5.8S rRNA RPL6 RPS3 FAU RPLP1 RPL11 RPLP0 RPL32 RPLP2 RPS10 RPL9 RPL39L RPL38 RPS3A RPS7 RPL36 EIF2S1:EIF2S2:EIF2S318S rRNA RPS24 RPL18A RPL36AL RPS12 RPS11 FAU RPS3A CEBPG RPS8 RPS19 GCN1 ATF4 RPL10A RPL38 RPL21 RPL19 RPSA RPL29 RPS25 RPS6 RPS2 RPL8 RPL26 CEBPB RPL12 RPL13 RPL35 RPL38 28S rRNA 28S rRNA GCN1 RPS7 RPS15A RPL23A RPL3 RPL17 RPS4Y1 RPL5 RPS5 CEBPG DDIT3 mRNARPS18 RPL13A 4, 37, 4423, 27, 331336


Description

EIF2AK4 (GCN2) senses amino acid deficiency by binding uncharged tRNAs near the ribosome and responds by phosphorylating EIF2S1, the alpha subunit of the translation initiation factor EIF2 (inferred from yeast homologs and mouse homologs, reviewed in Chaveroux et al. 2010, Castilho et al. 2014, Gallinetti et al. 2013, Bröer and Bröer 2017, Wek 2018). Phosphorylated EIF2S1 reduces translation of most mRNAs but increases translation of downstream ORFs in mRNAs such as ATF4 that contain upstream ORFs (inferred from mouse homologs in Vattem and Wek 2004, reviewed in Hinnebusch et al. 2016, Sonenberg and Hinnebusch 2009). ATF4, in turn, activates expression of genes involved in responding to amino acid deficiency such as DDIT3 (CHOP), ASNS (asparagine synthetase), CEBPB, and ATF3 (reviewed in Kilberg et al. 2012, Wortel et al. 2017). In mice, EIF2AK4 in the brain may responsible for avoidance of diets lacking essential amino acids (Hao et al. 2005, Maurin et al. 2005, see also Leib and Knight 2015, Gietzen et al. 2016, reviewed in Dever and Hinnebusch 2005).
EIF2AK4 is bound to both the ribosome and GCN1, which is required for activation of EIF2AK4 and may act by shuttling uncharged tRNAs from the A site of the ribosome to EIF2AK4. Upon binding tRNA, EIF2AK4 trans-autophosphorylates. Phosphorylated EIF2AK4 then phosphorylates EIF2S1 on serine-52, the same serine residue phosphorylated by other kinases of the integrated stress response: EIF2AK1 (HRI, activated by heme deficiency and other stresses), EIF2AK2 (PKR, activated by double-stranded RNA), and EIF2AK3 (PERK, activated by unfolded proteins) (reviewed in Hinnebusch 1994, Wek et al. 2006, Donnelly et al. 2013, Pakos-Zebrucka et al. 2016, Wek 2018), View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 9633012
Reactome-version 
Reactome version: 73
Reactome Author 
Reactome Author: May, Bruce

Try the New WikiPathways

View approved pathways at the new wikipathways.org.

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Guo L, Guo ZX, Gong HP, Shang YY, Zhong M, Zhang Y, Zhang W.; ''Tribbles homolog 3 is induced by high glucose and associated with apoptosis in human endothelial cells.''; PubMed Europe PMC Scholia
  2. Sikalidis AK, Lee JI, Stipanuk MH.; ''Gene expression and integrated stress response in HepG2/C3A cells cultured in amino acid deficient medium.''; PubMed Europe PMC Scholia
  3. Inglis AJ, Masson GR, Shao S, Perisic O, McLaughlin SH, Hegde RS, Williams RL.; ''Activation of GCN2 by the ribosomal P-stalk.''; PubMed Europe PMC Scholia
  4. Ord D, Ord T.; ''Characterization of human NIPK (TRB3, SKIP3) gene activation in stressful conditions.''; PubMed Europe PMC Scholia
  5. Chen C, Dudenhausen E, Chen H, Pan YX, Gjymishka A, Kilberg MS.; ''Amino-acid limitation induces transcription from the human C/EBPbeta gene via an enhancer activity located downstream of the protein coding sequence.''; PubMed Europe PMC Scholia
  6. Wek RC.; ''Role of eIF2α Kinases in Translational Control and Adaptation to Cellular Stress.''; PubMed Europe PMC Scholia
  7. Gjymishka A, Su N, Kilberg MS.; ''Transcriptional induction of the human asparagine synthetase gene during the unfolded protein response does not require the ATF6 and IRE1/XBP1 arms of the pathway.''; PubMed Europe PMC Scholia
  8. Blais JD, Filipenko V, Bi M, Harding HP, Ron D, Koumenis C, Wouters BG, Bell JC.; ''Activating transcription factor 4 is translationally regulated by hypoxic stress.''; PubMed Europe PMC Scholia
  9. Gallinetti J, Harputlugil E, Mitchell JR.; ''Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR.''; PubMed Europe PMC Scholia
  10. Podust LM, Krezel AM, Kim Y.; ''Crystal structure of the CCAAT box/enhancer-binding protein beta activating transcription factor-4 basic leucine zipper heterodimer in the absence of DNA.''; PubMed Europe PMC Scholia
  11. Wek RC, Jiang HY, Anthony TG.; ''Coping with stress: eIF2 kinases and translational control.''; PubMed Europe PMC Scholia
  12. Ross JA, Bressler KR, Thakor N.; ''Eukaryotic Initiation Factor 5B (eIF5B) Cooperates with eIF1A and eIF5 to Facilitate uORF2-Mediated Repression of ATF4 Translation.''; PubMed Europe PMC Scholia
  13. Hayner JN, Shan J, Kilberg MS.; ''Regulation of the ATF3 gene by a single promoter in response to amino acid availability and endoplasmic reticulum stress in human primary hepatocytes and hepatoma cells.''; PubMed Europe PMC Scholia
  14. Castilho BA, Shanmugam R, Silva RC, Ramesh R, Himme BM, Sattlegger E.; ''Keeping the eIF2 alpha kinase Gcn2 in check.''; PubMed Europe PMC Scholia
  15. Donnelly N, Gorman AM, Gupta S, Samali A.; ''The eIF2α kinases: their structures and functions.''; PubMed Europe PMC Scholia
  16. Chen H, Pan YX, Dudenhausen EE, Kilberg MS.; ''Amino acid deprivation induces the transcription rate of the human asparagine synthetase gene through a timed program of expression and promoter binding of nutrient-responsive basic region/leucine zipper transcription factors as well as localized histone acetylation.''; PubMed Europe PMC Scholia
  17. Bartlett JD, Luethy JD, Carlson SG, Sollott SJ, Holbrook NJ.; ''Calcium ionophore A23187 induces expression of the growth arrest and DNA damage inducible CCAAT/enhancer-binding protein (C/EBP)-related gene, gadd153. Ca2+ increases transcriptional activity and mRNA stability.''; PubMed Europe PMC Scholia
  18. Huggins CJ, Mayekar MK, Martin N, Saylor KL, Gonit M, Jailwala P, Kasoji M, Haines DC, Quiñones OA, Johnson PF.; ''C/EBPγ Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4.''; PubMed Europe PMC Scholia
  19. Armstrong JL, Flockhart R, Veal GJ, Lovat PE, Redfern CP.; ''Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells.''; PubMed Europe PMC Scholia
  20. Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM.; ''The integrated stress response.''; PubMed Europe PMC Scholia
  21. Carlson SG, Fawcett TW, Bartlett JD, Bernier M, Holbrook NJ.; ''Regulation of the C/EBP-related gene gadd153 by glucose deprivation.''; PubMed Europe PMC Scholia
  22. Leib DE, Knight ZA.; ''Re-examination of Dietary Amino Acid Sensing Reveals a GCN2-Independent Mechanism.''; PubMed Europe PMC Scholia
  23. Hua F, Mu R, Liu J, Xue J, Wang Z, Lin H, Yang H, Chen X, Hu Z.; ''TRB3 interacts with SMAD3 promoting tumor cell migration and invasion.''; PubMed Europe PMC Scholia
  24. Hinnebusch AG.; ''The eIF-2 alpha kinases: regulators of protein synthesis in starvation and stress.''; PubMed Europe PMC Scholia
  25. Xu J, Lv S, Qin Y, Shu F, Xu Y, Chen J, Xu BE, Sun X, Wu J.; ''TRB3 interacts with CtIP and is overexpressed in certain cancers.''; PubMed Europe PMC Scholia
  26. Hao S, Sharp JW, Ross-Inta CM, McDaniel BJ, Anthony TG, Wek RC, Cavener DR, McGrath BC, Rudell JB, Koehnle TJ, Gietzen DW.; ''Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex.''; PubMed Europe PMC Scholia
  27. Bruhat A, Jousse C, Wang XZ, Ron D, Ferrara M, Fafournoux P.; ''Amino acid limitation induces expression of CHOP, a CCAAT/enhancer binding protein-related gene, at both transcriptional and post-transcriptional levels.''; PubMed Europe PMC Scholia
  28. Kilberg MS, Balasubramanian M, Fu L, Shan J.; ''The transcription factor network associated with the amino acid response in mammalian cells.''; PubMed Europe PMC Scholia
  29. Sonenberg N, Hinnebusch AG.; ''Regulation of translation initiation in eukaryotes: mechanisms and biological targets.''; PubMed Europe PMC Scholia
  30. Bruhat A, Chérasse Y, Maurin AC, Breitwieser W, Parry L, Deval C, Jones N, Jousse C, Fafournoux P.; ''ATF2 is required for amino acid-regulated transcription by orchestrating specific histone acetylation.''; PubMed Europe PMC Scholia
  31. Örd D, Örd T, Biene T, Örd T.; ''TRIB3 increases cell resistance to arsenite toxicity by limiting the expression of the glutathione-degrading enzyme CHAC1.''; PubMed Europe PMC Scholia
  32. Fu L, Kilberg MS.; ''Elevated cJUN expression and an ATF/CRE site within the ATF3 promoter contribute to activation of ATF3 transcription by the amino acid response.''; PubMed Europe PMC Scholia
  33. Siu F, Chen C, Zhong C, Kilberg MS.; ''CCAAT/enhancer-binding protein-beta is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene.''; PubMed Europe PMC Scholia
  34. Vattem KM, Wek RC.; ''Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells.''; PubMed Europe PMC Scholia
  35. Jousse C, Bruhat A, Carraro V, Urano F, Ferrara M, Ron D, Fafournoux P.; ''Inhibition of CHOP translation by a peptide encoded by an open reading frame localized in the chop 5'UTR.''; PubMed Europe PMC Scholia
  36. Hinnebusch AG, Ivanov IP, Ivanov IP, Sonenberg N.; ''Translational control by 5'-untranslated regions of eukaryotic mRNAs.''; PubMed Europe PMC Scholia
  37. Dever TE, Hinnebusch AG.; ''GCN2 whets the appetite for amino acids.''; PubMed Europe PMC Scholia
  38. Averous J, Bruhat A, Jousse C, Carraro V, Thiel G, Fafournoux P.; ''Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation.''; PubMed Europe PMC Scholia
  39. Bröer S, Bröer A.; ''Amino acid homeostasis and signalling in mammalian cells and organisms.''; PubMed Europe PMC Scholia
  40. Bruhat A, Jousse C, Carraro V, Reimold AM, Ferrara M, Fafournoux P.; ''Amino acids control mammalian gene transcription: activating transcription factor 2 is essential for the amino acid responsiveness of the CHOP promoter.''; PubMed Europe PMC Scholia
  41. Chaveroux C, Lambert-Langlais S, Cherasse Y, Averous J, Parry L, Carraro V, Jousse C, Maurin AC, Bruhat A, Fafournoux P.; ''Molecular mechanisms involved in the adaptation to amino acid limitation in mammals.''; PubMed Europe PMC Scholia
  42. Balasubramanian MN, Shan J, Kilberg MS.; ''Dynamic changes in genomic histone association and modification during activation of the ASNS and ATF3 genes by amino acid limitation.''; PubMed Europe PMC Scholia
  43. Lee JI, Dominy JE, Sikalidis AK, Hirschberger LL, Wang W, Stipanuk MH.; ''HepG2/C3A cells respond to cysteine deprivation by induction of the amino acid deprivation/integrated stress response pathway.''; PubMed Europe PMC Scholia
  44. Gietzen DW, Anthony TG, Fafournoux P, Maurin AC, Koehnle TJ, Hao S.; ''Measuring the Ability of Mice to Sense Dietary Essential Amino Acid Deficiency: The Importance of Amino Acid Status and Timing.''; PubMed Europe PMC Scholia
  45. Wortel IMN, van der Meer LT, Kilberg MS, van Leeuwen FN.; ''Surviving Stress: Modulation of ATF4-Mediated Stress Responses in Normal and Malignant Cells.''; PubMed Europe PMC Scholia
  46. Lee SH, Min KW, Zhang X, Baek SJ.; ''3,3'-diindolylmethane induces activating transcription factor 3 (ATF3) via ATF4 in human colorectal cancer cells.''; PubMed Europe PMC Scholia
  47. Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H.; ''TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death.''; PubMed Europe PMC Scholia
  48. Maurin AC, Jousse C, Averous J, Parry L, Bruhat A, Cherasse Y, Zeng H, Zhang Y, Harding HP, Ron D, Fafournoux P.; ''The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores.''; PubMed Europe PMC Scholia
  49. Chérasse Y, Maurin AC, Chaveroux C, Jousse C, Carraro V, Parry L, Deval C, Chambon C, Fafournoux P, Bruhat A.; ''The p300/CBP-associated factor (PCAF) is a cofactor of ATF4 for amino acid-regulated transcription of CHOP.''; PubMed Europe PMC Scholia
  50. Pan YX, Chen H, Thiaville MM, Kilberg MS.; ''Activation of the ATF3 gene through a co-ordinated amino acid-sensing response programme that controls transcriptional regulation of responsive genes following amino acid limitation.''; PubMed Europe PMC Scholia

History

CompareRevisionActionTimeUserComment
114695view16:17, 25 January 2021ReactomeTeamReactome version 75
113140view11:20, 2 November 2020ReactomeTeamReactome version 74
112785view17:41, 9 October 2020DeSlOntology Term : 'pathway pertinent to DNA replication and repair, cell cycle, maintenance of genomic integrity, RNA and protein biosynthesis' added !
112741view16:14, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
18S rRNA ProteinX03205 (EMBL)
28S rRNA ProteinM11167 (EMBL)
5.8S rRNA ProteinJ01866 (EMBL)
5S rRNA ProteinV00589 (EMBL)
ADPMetaboliteCHEBI:456216 (ChEBI)
ASNS gene ProteinENSG00000070669 (Ensembl)
ASNS geneGeneProductENSG00000070669 (Ensembl)
ASNSProteinP08243 (Uniprot-TrEMBL)
ATF3 gene ProteinENSG00000162772 (Ensembl)
ATF3 geneGeneProductENSG00000162772 (Ensembl)
ATF3ProteinP18847 (Uniprot-TrEMBL)
ATF4 dimer:p-T69,T71-ATF2 dimer:DDIT3 geneComplexR-HSA-9635843 (Reactome)
ATF4 ProteinP18848 (Uniprot-TrEMBL)
ATF4 mRNARnaENST00000404241 (Ensembl)
ATF4:ATF3 geneComplexR-HSA-9635905 (Reactome)
ATF4:CEBPB geneComplexR-HSA-9635875 (Reactome)
ATF4:CEBPB,CEBPG,DDIT3:TRIB3 geneComplexR-HSA-9635876 (Reactome)
ATF4:CEBPB,CEBPG:ASNS geneComplexR-HSA-9635898 (Reactome)
ATF4ProteinP18848 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)
CEBPB ProteinP17676 (Uniprot-TrEMBL)
CEBPB gene ProteinENSG00000172216 (Ensembl)
CEBPB geneGeneProductENSG00000172216 (Ensembl)
CEBPB,CEBPG,DDIT3ComplexR-HSA-9654226 (Reactome)
CEBPB,CEBPGComplexR-HSA-9658331 (Reactome)
CEBPBProteinP17676 (Uniprot-TrEMBL)
CEBPG ProteinP53567 (Uniprot-TrEMBL)
DDIT3 ProteinP35638 (Uniprot-TrEMBL)
DDIT3 gene ProteinENSG00000175197 (Ensembl)
DDIT3 geneGeneProductENSG00000175197 (Ensembl)
DDIT3 mRNARnaENST00000346473 (Ensembl)
DDIT3ProteinP35638 (Uniprot-TrEMBL)
EIF2AK4 ProteinQ9P2K8 (Uniprot-TrEMBL)
EIF2AK4:GCN1:80S ribosome:mRNAComplexR-HSA-9633014 (Reactome)
EIF2S1 ProteinP05198 (Uniprot-TrEMBL)
EIF2S1:EIF2S2:EIF2S3ComplexR-HSA-72515 (Reactome)
EIF2S2 ProteinP20042 (Uniprot-TrEMBL)
EIF2S3 ProteinP41091 (Uniprot-TrEMBL)
FAU ProteinP62861 (Uniprot-TrEMBL)
GCN1 ProteinQ92616 (Uniprot-TrEMBL)
GCN1:80S ribosome:mRNAComplexR-HSA-9634679 (Reactome)
IMPACT ProteinQ9P2X3 (Uniprot-TrEMBL)
IMPACT:GCN1:80S ribosome:mRNAComplexR-HSA-9634665 (Reactome)
IMPACTProteinQ9P2X3 (Uniprot-TrEMBL)
RPL10 ProteinP27635 (Uniprot-TrEMBL)
RPL10A ProteinP62906 (Uniprot-TrEMBL)
RPL10L ProteinQ96L21 (Uniprot-TrEMBL)
RPL11 ProteinP62913 (Uniprot-TrEMBL)
RPL12 ProteinP30050 (Uniprot-TrEMBL)
RPL13 ProteinP26373 (Uniprot-TrEMBL)
RPL13A ProteinP40429 (Uniprot-TrEMBL)
RPL14 ProteinP50914 (Uniprot-TrEMBL)
RPL15 ProteinP61313 (Uniprot-TrEMBL)
RPL17 ProteinP18621 (Uniprot-TrEMBL)
RPL18 ProteinQ07020 (Uniprot-TrEMBL)
RPL18A ProteinQ02543 (Uniprot-TrEMBL)
RPL19 ProteinP84098 (Uniprot-TrEMBL)
RPL21 ProteinP46778 (Uniprot-TrEMBL)
RPL22 ProteinP35268 (Uniprot-TrEMBL)
RPL22L1 ProteinQ6P5R6 (Uniprot-TrEMBL)
RPL23 ProteinP62829 (Uniprot-TrEMBL)
RPL23A ProteinP62750 (Uniprot-TrEMBL)
RPL24 ProteinP83731 (Uniprot-TrEMBL)
RPL26 ProteinP61254 (Uniprot-TrEMBL)
RPL26L1 ProteinQ9UNX3 (Uniprot-TrEMBL)
RPL27 ProteinP61353 (Uniprot-TrEMBL)
RPL27A ProteinP46776 (Uniprot-TrEMBL)
RPL28 ProteinP46779 (Uniprot-TrEMBL)
RPL29 ProteinP47914 (Uniprot-TrEMBL)
RPL3 ProteinP39023 (Uniprot-TrEMBL)
RPL30 ProteinP62888 (Uniprot-TrEMBL)
RPL31 ProteinP62899 (Uniprot-TrEMBL)
RPL32 ProteinP62910 (Uniprot-TrEMBL)
RPL34 ProteinP49207 (Uniprot-TrEMBL)
RPL35 ProteinP42766 (Uniprot-TrEMBL)
RPL35A ProteinP18077 (Uniprot-TrEMBL)
RPL36 ProteinQ9Y3U8 (Uniprot-TrEMBL)
RPL36A ProteinP83881 (Uniprot-TrEMBL)
RPL36AL ProteinQ969Q0 (Uniprot-TrEMBL)
RPL37 ProteinP61927 (Uniprot-TrEMBL)
RPL37A ProteinP61513 (Uniprot-TrEMBL)
RPL38 ProteinP63173 (Uniprot-TrEMBL)
RPL39 ProteinP62891 (Uniprot-TrEMBL)
RPL39L ProteinQ96EH5 (Uniprot-TrEMBL)
RPL3L ProteinQ92901 (Uniprot-TrEMBL)
RPL4 ProteinP36578 (Uniprot-TrEMBL)
RPL40 ProteinP62987 (Uniprot-TrEMBL)
RPL41 ProteinP62945 (Uniprot-TrEMBL)
RPL5 ProteinP46777 (Uniprot-TrEMBL)
RPL6 ProteinQ02878 (Uniprot-TrEMBL)
RPL7 ProteinP18124 (Uniprot-TrEMBL)
RPL7A ProteinP62424 (Uniprot-TrEMBL)
RPL8 ProteinP62917 (Uniprot-TrEMBL)
RPL9 ProteinP32969 (Uniprot-TrEMBL)
RPLP0 ProteinP05388 (Uniprot-TrEMBL)
RPLP1 ProteinP05386 (Uniprot-TrEMBL)
RPLP2 ProteinP05387 (Uniprot-TrEMBL)
RPS10 ProteinP46783 (Uniprot-TrEMBL)
RPS11 ProteinP62280 (Uniprot-TrEMBL)
RPS12 ProteinP25398 (Uniprot-TrEMBL)
RPS13 ProteinP62277 (Uniprot-TrEMBL)
RPS14 ProteinP62263 (Uniprot-TrEMBL)
RPS15 ProteinP62841 (Uniprot-TrEMBL)
RPS15A ProteinP62244 (Uniprot-TrEMBL)
RPS16 ProteinP62249 (Uniprot-TrEMBL)
RPS17 ProteinP08708 (Uniprot-TrEMBL)
RPS18 ProteinP62269 (Uniprot-TrEMBL)
RPS19 ProteinP39019 (Uniprot-TrEMBL)
RPS2 ProteinP15880 (Uniprot-TrEMBL)
RPS20 ProteinP60866 (Uniprot-TrEMBL)
RPS21 ProteinP63220 (Uniprot-TrEMBL)
RPS23 ProteinP62266 (Uniprot-TrEMBL)
RPS24 ProteinP62847 (Uniprot-TrEMBL)
RPS25 ProteinP62851 (Uniprot-TrEMBL)
RPS26 ProteinP62854 (Uniprot-TrEMBL)
RPS27 ProteinP42677 (Uniprot-TrEMBL)
RPS27A(77-156) ProteinP62979 (Uniprot-TrEMBL)
RPS27L ProteinQ71UM5 (Uniprot-TrEMBL)
RPS28 ProteinP62857 (Uniprot-TrEMBL)
RPS29 ProteinP62273 (Uniprot-TrEMBL)
RPS3 ProteinP23396 (Uniprot-TrEMBL)
RPS3A ProteinP61247 (Uniprot-TrEMBL)
RPS4X ProteinP62701 (Uniprot-TrEMBL)
RPS4Y1 ProteinP22090 (Uniprot-TrEMBL)
RPS4Y2 ProteinQ8TD47 (Uniprot-TrEMBL)
RPS5 ProteinP46782 (Uniprot-TrEMBL)
RPS6 ProteinP62753 (Uniprot-TrEMBL)
RPS7 ProteinP62081 (Uniprot-TrEMBL)
RPS8 ProteinP62241 (Uniprot-TrEMBL)
RPS9 ProteinP46781 (Uniprot-TrEMBL)
RPSA ProteinP08865 (Uniprot-TrEMBL)
TRIB3 gene ProteinENSG00000101255 (Ensembl)
TRIB3 geneGeneProductENSG00000101255 (Ensembl)
TRIB3ProteinQ96RU7 (Uniprot-TrEMBL)
mRNA R-HSA-72323 (Reactome)
p-S52-EIF2S1 ProteinP05198 (Uniprot-TrEMBL)
p-S52-EIF2S1:EIF2S2:EIF2S3ComplexR-HSA-9633006 (Reactome)
p-T69,T71-ATF2 ProteinP15336 (Uniprot-TrEMBL)
p-T69,T71-ATF2ProteinP15336 (Uniprot-TrEMBL)
p-T899-EIF2AK4 ProteinQ9P2K8 (Uniprot-TrEMBL)
tRNA R-HSA-141679 (Reactome)
tRNA:EIF2AK4:GCN1:80S Ribosome:mRNAComplexR-HSA-9633013 (Reactome)
tRNA:p-T899-EIF2AK4:GCN1:80S Ribosome:mRNAComplexR-HSA-9633821 (Reactome)
tRNAR-HSA-141679 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-9633008 (Reactome)
ADPArrowR-HSA-9633742 (Reactome)
ASNS geneR-HSA-1791118 (Reactome)
ASNS geneR-HSA-9635915 (Reactome)
ASNSArrowR-HSA-1791118 (Reactome)
ATF3 geneR-HSA-1791173 (Reactome)
ATF3 geneR-HSA-9635892 (Reactome)
ATF3ArrowR-HSA-1791173 (Reactome)
ATF4 dimer:p-T69,T71-ATF2 dimer:DDIT3 geneArrowR-HSA-9635804 (Reactome)
ATF4 dimer:p-T69,T71-ATF2 dimer:DDIT3 geneArrowR-HSA-9644926 (Reactome)
ATF4 mRNAR-HSA-381128 (Reactome)
ATF4:ATF3 geneArrowR-HSA-1791173 (Reactome)
ATF4:ATF3 geneArrowR-HSA-9635892 (Reactome)
ATF4:CEBPB geneArrowR-HSA-9635918 (Reactome)
ATF4:CEBPB geneArrowR-HSA-9635936 (Reactome)
ATF4:CEBPB,CEBPG,DDIT3:TRIB3 geneArrowR-HSA-9635912 (Reactome)
ATF4:CEBPB,CEBPG,DDIT3:TRIB3 geneArrowR-HSA-9635927 (Reactome)
ATF4:CEBPB,CEBPG:ASNS geneArrowR-HSA-1791118 (Reactome)
ATF4:CEBPB,CEBPG:ASNS geneArrowR-HSA-9635915 (Reactome)
ATF4ArrowR-HSA-381128 (Reactome)
ATF4R-HSA-9635804 (Reactome)
ATF4R-HSA-9635892 (Reactome)
ATF4R-HSA-9635915 (Reactome)
ATF4R-HSA-9635927 (Reactome)
ATF4R-HSA-9635936 (Reactome)
ATPR-HSA-9633008 (Reactome)
ATPR-HSA-9633742 (Reactome)
CEBPB geneR-HSA-9635918 (Reactome)
CEBPB geneR-HSA-9635936 (Reactome)
CEBPB,CEBPG,DDIT3R-HSA-9635927 (Reactome)
CEBPB,CEBPGR-HSA-9635915 (Reactome)
CEBPBArrowR-HSA-9635918 (Reactome)
DDIT3 geneR-HSA-9635804 (Reactome)
DDIT3 geneR-HSA-9644926 (Reactome)
DDIT3 mRNAArrowR-HSA-9644926 (Reactome)
DDIT3 mRNAR-HSA-9650722 (Reactome)
DDIT3ArrowR-HSA-9650722 (Reactome)
EIF2AK4:GCN1:80S ribosome:mRNAR-HSA-9633005 (Reactome)
EIF2S1:EIF2S2:EIF2S3R-HSA-9633008 (Reactome)
GCN1:80S ribosome:mRNAR-HSA-9634669 (Reactome)
IMPACT:GCN1:80S ribosome:mRNAArrowR-HSA-9634669 (Reactome)
IMPACTR-HSA-9634669 (Reactome)
R-HSA-1791118 (Reactome) The Asparagine Synthetase (ASNS) gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Chen et al. 2004, Lee et al. 2008, Gjymishka et al. 2009, Sikalidis et al. 2011, Balasubramanian et al. 2013, inferred from the mouse homolog). Transcription of ASNS is activated by the unfolded protein response (Gjymishka et al. 2009), amino acid deficiency (Chen et al. 2004, Lee et al. 2008, Sikalidis et al. 2011, Balasubramanian et al. 2013, inferred from the mouse homolog), and heme deficiency (inferred from the mouse homolog).
R-HSA-1791173 (Reactome) The ATF3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Chen et al. 2004, Pan et al. 2007, Lee et al. 2008, Armstrong et al. 2010, Sikalidis et al. 2011, Fu and Kilberg 2013, Lee et al. 2013, Hayner et al. 2018). Transcription of ATF3 is enhanced in response to amino acid deficiency (Chen et al. 2004, Pan et al. 2007, Lee et al. 2008, Sikaldis et al. 2011, Fu and Kilberg 2013, Hayner et al. 2018). ATF4 binds a CEBP-ATF response element (CARE) and an additional upstream element in the promoter of the ATF3 gene, resulting in enhanced transcription (Pan et al. 2007, Armstrong et al. 2010, Fu and Kilberg 2013, Lee et al. 2013, Hayner et al. 2018, and inferred from mouse homologs). CEBPB and ATF3 bind later and correlate with reduced expression of ATF4 (Pan et al. 2007)
R-HSA-381128 (Reactome) ATF4 mRNA is translated to yield ATF4 protein, which then transits to the nucleus (Blais et al. 2004, Ross et al. 2018). The mRNA of ATF4 contains 2 upstream ORFs (uORFs) (Ross et al. 2018 and inferred from the mouse homolog). The second uORF overlaps the ORF encoding ATF4 and thus prevents translation of ATF4. When EIF2S1 (eIF2-alpha) is phosphorylated, translation initiation is decreased overall, translation of the uORFs is suppressed, and translation of the ORF encoding ATF4 is increased (Blais et al. 2004, Ross et al. 2018, and inferred from mouse homologs).
R-HSA-9633005 (Reactome) The histidyl-tRNA synthetase-like domain of EIF2AK4 (GCN2) binds uncharged tRNA, resulting in activation of the protein kinase domain of EIF2AK4 (Inglis et al. 2019 and inferred from yeast homologs and mouse homologs). In the absence of tRNA, EIF2AK4 appears to exist in an equilibrium between antiparallel and parallel dimers. Upon binding tRNA, the parallel dimer is stabilized and the C-terminal domain shifts away from the protein kinase domain, resulting in activation of the kinase activity of EIF2AK4 (inferred from GCN2, the yeast homolog).
EIF2AK4 interacts with GCN1 and the P-stalk of ribosomes (Inglis et al. 2019), though the interaction between mammalian EIF2AK4 and ribosomes is not as stable as the interaction between yeast GCN2 and ribosomes (inferred from yeast homologs and mouse homologs). By such transient interactions, a population of EIF2AK4 may sample a larger population of ribosomes for uncharged tRNAs. The interaction between EIF2AK4 and GCN1 is required for efficient phosphorylation of EIF2S1 by EIF2AK4 and GCN1 may act to transfer uncharged tRNAs from the A site of the ribosome to EIF2AK4 (inferred from yeast homologs and mouse homologs).
R-HSA-9633008 (Reactome) After binding uncharged tRNA and autophosphorylating, EIF2AK4 (GCN2) phosphorylates EIF2S1 (eIF2 alpha subunit) on serine-52 (serine-51 in the rabbit homolog, inferred from mouse homologs and yeast homologs), which inhibits the guanine nucleotide exchange factor eIF2B, impairs exchange of GDP for GTP, and reduces recycling of EIF2 for initiation of translation. This causes downregulation of translation of most mRNAs, however translation of certain mRNAs possessing upstream ORFs, such as ATF4, is upregulated (inferred from mouse homologs and yeast homologs).
R-HSA-9633742 (Reactome) After binding uncharged tRNA, the EIF2AK4 (GCN2) dimer trans-autophosphorylates on threonine-899, resulting in activation of the kinase domain of EIF2AK4 (Harding et al. 2000, Deng et al. 2002, Cambiaghi et al. 2014, and inferred from mouse homologs and yeast homologs).
R-HSA-9634669 (Reactome) IMPACT, a mammalian homolog of yeast YIH1, competes with EIF2AK4 (GCN2) for binding to GCN1, which is required for activation of EIF2AK4 and may act by transferring unacylated tRNAs from the ribosome to EIF2AK4 (inferred from mouse homologs). IMPACT thereby inhibits phosphorylation of EIF2A by EIF2AK4 in response to amino acid deficiency (inferred from mouse homologs). IMPACT is preferentially expressed in neurons, associates with translating ribosomes, enhances translation initiation, and promotes neuritogenesis (inferred from mouse homologs).
R-HSA-9635804 (Reactome) The promoter of the DDIT3 (CHOP) gene contains an Amino Acid Response Element (AARE) that binds ATF4 and ATF2. ATF2 and ATF4 are required for full activation of gene transcription in response to amino acid deprivation (Bruhat et al. 2000, Averous et al. 2004). Phospho-ATF2 is essential in the acetylation of histone H4 and H2B (Bruhat et al. 2007). ATF4 recruits PCAF to enhance transcription (Chérasse et al. 2007). ATF4 appears to be a monomer in the absence of DNA and a dimer after binding DNA (Podust et al. 2001).
R-HSA-9635892 (Reactome) ATF4 binds an amino acid response element (AARE) in the promoter of the ATF3 gene (Chen et al. 2004, Pan et al. 2007, Fu and Kilberg 2013, Hayner et al. 2018). ATF4 initially binds the ATF3 promoter with phosphorylated ATF2, then with JUN (c-Jun), then with CEBPB (Fu and Kilberg 2013, Hayner et al. 2018). ATF3 and CEBPB bind later and correlate with reduced expression of ATF3 (Pan et al. 2007, Fu and Kilberg 2013, Hayner et al. 2018).
R-HSA-9635912 (Reactome) The TRIB3 (TRB3, NIPK) gene is transcribed to yield mRNA and the mRNA is translated to yield TRIB3 protein (Ohoka et al. 2005, Ord and Ord 2005, Lee et al. 2008, Sikalidis et al. 2011, Ord et al. 2016, and inferred from the mouse homolog). Transcription of TRIB3 is enhanced in response to amino acid deficiency (Lee et al. 2008, Sikalidis et al. 2011, and inferred from mouse homologs), endoplasmic reticulum stress (Ohoka et al. 2005, Ord and Ord 2005), oxidative stress (Ord and Ord 2005, Ord et al. 2016) and heme deficiency (inferred from mouse homologs). ATF4 bound with a CEBP family protein to the promoter of TRIB3 (NIPK, TRB3) enhances transcription of TRIB3 (Ohoka et al. 2005, Ord and Ord 2005, Lee et al. 2008, Sikalidis et al. 2011, Ord et al. 2016, and inferred from mouse homologs).
R-HSA-9635915 (Reactome) ATF4 and CEBPB or CEBPG bind a CEBP-ATF regulatory element (CARE) in the promoter of the ASNS gene (Siu et al 2001, Chen et al. 2004, inferred from mouse homologs). ATF4 binds rapidly during the first 2 hours after amino acid deprivation (Chen et al. 2004). ATF3 and CEBPB accumulate on the ASNS promoter more slowly and appear to correlate with decreasing transcription of ASNS (Chen et al. 2004). EIF2AK1 acts via ATF4 to activate transcription of ASNS in response to heme deficiency (inferred from mouse homologs).
R-HSA-9635918 (Reactome) The CEBPB gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Chen et al. 2005, Lee et al. 2008, Sikalidis et al. 2011). Transcription of CEBPB is activated in response to amino acid deficiency (Chen et al. 2005, Lee et al. 2008, Sikalidis et al. 2011). ATF4 bound to an enhancer downstream of the CEBPB coding region (Chen et al. 2005) increases transcription of CEBPB approximately 4-fold (Chen et al. 2005, Lee et al. 2008, Sikalidis et al. 2011).
R-HSA-9635927 (Reactome) ATF4 binds composite CEBP-ATF elements located in three 33-bp tandem repeats in the promoter of the TRIB3 (TRB3, NIPK) gene (Ohoka et al. 2005, Ord and Ord 2005). ATF4 cooperates with DDIT3 to activate TRIB3 promoter activity (Ohoka et al. 2005). ATF4 also appears to bind as a heterodimer with CEBPB or CEBPG, which is required for full response to amino acid deficiency (inferred from mouse homologs).
R-HSA-9635936 (Reactome) ATF4 binds an enhancer downstream of the protein coding region of the CEBPB gene (Chen et al. 2005). The binding site resembles a composite CEBP-ATF element. Therefore ATF4 may form a heterodimer with a CEBP protein at the element (Chen et al. 2005).
R-HSA-9644926 (Reactome) The DDIT3 (CHOP) gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Bartlett et al. 1992, Carlson et al. 1993, Bruhat et al. 1997, Yoshida et al. 2000, Lee et al. 2008, Sikalidis et al. 2011). In response to amino acid starvation, transcription of DDIT3 s enhanced by ATF4 and phosphorylated ATF2 (Bruhat et al. 2000, Averous et al. 2004, Bruhat et al. 2007)
R-HSA-9650722 (Reactome) The DDIT3 mRNA is translated to yield DDIT3 (CHOP) protein (Jousse et al. 2001, and inferred from the mouse homolog), which is then imported into the nucleus. The mRNA of DDIT3 contains an upstream ORF (uORF) which has a start codon in an unfavorable context (Jousse et al. 2001, and inferred from the mouse homolog), resulting in low expression of the downstream DDIT3 coding region. When EIF2S1 (eIF2-alpha) is phosphorylated in response to stress, translation of the uORF is suppressed and translation of DDIT3 is increased (inferred from the mouse homolog).
TRIB3 geneR-HSA-9635912 (Reactome)
TRIB3 geneR-HSA-9635927 (Reactome)
TRIB3ArrowR-HSA-9635912 (Reactome)
p-S52-EIF2S1:EIF2S2:EIF2S3ArrowR-HSA-381128 (Reactome)
p-S52-EIF2S1:EIF2S2:EIF2S3ArrowR-HSA-9633008 (Reactome)
p-S52-EIF2S1:EIF2S2:EIF2S3ArrowR-HSA-9650722 (Reactome)
p-T69,T71-ATF2R-HSA-9635804 (Reactome)
tRNA:EIF2AK4:GCN1:80S Ribosome:mRNAArrowR-HSA-9633005 (Reactome)
tRNA:EIF2AK4:GCN1:80S Ribosome:mRNAR-HSA-9633742 (Reactome)
tRNA:EIF2AK4:GCN1:80S Ribosome:mRNAmim-catalysisR-HSA-9633742 (Reactome)
tRNA:p-T899-EIF2AK4:GCN1:80S Ribosome:mRNAArrowR-HSA-9633742 (Reactome)
tRNA:p-T899-EIF2AK4:GCN1:80S Ribosome:mRNAmim-catalysisR-HSA-9633008 (Reactome)
tRNAR-HSA-9633005 (Reactome)
Personal tools